Et2AlCl-catalyzed cyclization of epoxytrichloroacetimidates for the synthesis of α-substituted serines

Full text of DOI:10.1021/jo9618278

J . Org. Chem. 1997, 62, 2275-2279
2275
Sch em e 1
Et2AlCl-Ca ta lyzed Cycliza tion of
Ep oxytr ich lor oa cetim id a tes for th e
Syn th esis of r-Su bstitu ted Ser in es
Susumi Hatakeyama,* Hiromitsu Matsumoto,
Hiroko Fukuyama, Yasuko Mukugi, and Hiroshi Irie
Sch em e 2
Faculty of Pharmaceutical Sciences, Nagasaki University,
Nagasaki 852, J apan
Received September 24, 1996
In recent years much attention has been focused on
the synthesis of R-substituted R-amino acids particularly
in view of the design and the synthesis of enzyme
inhibitors.1 In connection with a project directed toward
the synthesis of biologically interesting natural products
such as conagenin, lactacystin, and myriocin,2 we needed
a promising method for the preparation of R-substituted
serine structures. Our strategy for the preparation of
R-substituted serines relies on acid-catalyzed cyclization
of 2-substituted 2,3-epoxytrichloroacetimidates as de-
picted in Scheme 1. Schmidt’s pioneering work3 on this
type of cyclization tells us that the degree of the regio-
selectivity varies depending upon the structure of the
substrate and the acid catalyst used. We, therefore,
undertook detailed investigation of acid-catalyzed cy-
clizations of various 2-methyl-2,3-epoxytrichloroacetimi-
dates which have not been examined before.4 We now
report the results of the cyclizations and also the syn-
thesis of both methyl (R)- and (S)-N-Boc-methylserinates
based on the above-mentioned strategy.
Ta ble 1. Et2AlCl- a n d BF 3‚Et2O-Ca ta lyzed Rea ction s of
2-Meth yl-2,3-ep oxytr ich lor oa cetim id a tes
The required 2,3-epoxytrichloroacetimidates 2 were
easily prepared by the reaction of the corresponding
epoxy alcohols 15 with trichloroacetonitrile in the pres-
ence of a catalytic amount of DBU (Scheme 2).3 Their
acid catalyzed cyclizations were examined under various
conditions, and Et2AlCl was eventually found to be a
superior catalyst in this particular reaction as shown in
Table 1.6 Upon treatment of 2-methyl-2,3-epoxytrichloro-
acetimidates 2a -d with 0.5 equiv of Et2AlCl in CH2Cl2
(1) For recent syntheses of R-substituted R-amino acids, see: (a)
Coloson, P.-J .; Hegedus, L. S. J . Org. Chem. 1993, 58, 5918-5924. (b)
Moon, S.-H.; Ohfune, Y. J . Am. Chem. Soc. 1994, 116, 7405-7406. (c)
Shao, H.; Zhu, Q.; Goodman, M. J . Org. Chem. 1995, 60, 790-791. (d)
Wipf, P.; Venkatraman, S.; Miller, C. P. Tetrahedron Lett. 1995, 36,
3639-3642. (e) Berkowitz, D. B.; Smith, M. K. J . Org. Chem. 1995,
60, 1233-1238. (f) Sano, S.; Liu, X.-K.; Takebayashi, M.; Kobayashi,
Y.; Tabata, K.; Shiro, M.; Nagao, Y. Tetrahedron Lett. 1995, 36, 4101-
4104.
(2) For recent syntheses of natural products indicated, see the
following references. (a) Conagenin: Hatakeyama, S.; Fukuyama, H.;
Mukugi, Y.; Irie, H. Tetrahedron Lett. 1996, 37, 4047-4050. (b)
Lactacystin: Corey, E. J .; Reichard, G. A. J . Am. Chem. Soc. 1992,
114, 10677-10678. Sunazuka, T.; Nagamitsu, T.; Matsuzaki, K.;
Tanaka, H.; Omura, S. J . Am. Chem. Soc. 1993, 115, 5302. Uno, H.;
Baldwin, J . E.; Russell, A. T. J . Am. Chem. Soc. 1994, 116, 2139-
2140. Chida, N.; Takeoka, J .; Tsutsumi, N.; Ogawa, S. J . Chem. Soc.,
Chem. Commun. 1995, 793-794. (c) Myriocin: Yoshikawa, M.; Yokoka-
wa, Y.; Okuno, Y.; Murakami, N. Tetrahedron 1995, 51, 6209-6228.
Sano, S.; Kobayashi, Y.; Kondo, T.; Takebayashi, M.; Murayama, S.;
Fujita, T.; Nagao, Y. Tetrahedron Lett. 1995, 36, 2097-2100.
(3) Schmidt, U.; Respondek, M.; Lieberknecht, A.; Werner, J .; Fisher,
P. Synthesis 1989, 256-261.
(4) For Lewis acid catalyzed cyclization of epoxytrichloroacetimi-
dates, see: ref 3 and the following. (a) Bernet, B.; Vasella, A.
Tetrahedron Lett. 1983, 49, 5491-176. (b) Schmidt, U.; Za¨h, M.;
Lieberknecht, A. J . Chem. Soc., Chem. Commun. 1991, 1002-1004.
(c) Hart, T. W.; Vacher, B. Tetrahedron Lett. 1992, 33, 3009-3012.
(5) Prepared in optically active forms (g95% ee) from the corre-
sponding allylic alcohols by Katsuki-Sharpless catalytic asymmetric
epoxidation except racemic 2d . Cf.: Gao,Y.; Hanson, R. M.; Klunder,
J . M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J . Am. Chem. Soc.
1987, 109, 5765-5780.
at room temperature, the cyclizations took place at the
C-2 quaternary center of the epoxide to give the oxazo-
lines 3a -d exclusively (entries 1, 3, 5, and 7). In the
cases of 2e and 2f, the cyclizations occurred in poor
regioselectivity to yield a mixture of oxazoline 3 and
(6) The stereochemistries of 3a -c and 3e were determined by NOE
experiment (500 MHz 1H NMR) of the corresponding acetonides of
5a -c and 5e which were prepared from 3a -c and 3e by acid
hydrolysis. The stereochemistries of 3d and 4e were determined by
NOE experiments (500 MHz 1H NMR). The structure of 6e was also
confirmed by hydrolytic transformation of 4e into 6e.
S0022-3263(96)01827-0 CCC: $14.00 © 1997 American Chemical Society

2276 J . Org. Chem., Vol. 62, No. 7, 1997
Notes
Ta ble 2. Et2AlCl- a n d BF 3‚Et2O-Ca ta lyzed Rea ction s of
Sch em e 3
2-Un su bstitu ted 2,3-Ep oxytr ich lor oa cetim id a tes
Sch em e 4
dihydrooxazine 4 due to the existence of the phenyl group
or two methyl groups at the 3-position (entries 9 and 11).
These results suggest that the cyclization takes place
preferentially at the more polarized center of the epoxide
with complete inversion of the stereochemistry under
these conditions. It can be seen also that BF3‚Et2O is
another catalyst of choice (entries 2, 4, 6, 8, 10, and 12).
However, BF3‚Et2O-catalyzed reactions always produced
the trichloroacetamides 5 or 67 together with cyclized
products 3 or 4 even under strictly anhydrous conditions
while Et2AlCl-catalyzed reactions allowed the exclusive
formation of cyclized products 3 and 4. Other catalyst
such as TiCl4, SnCl4, TMSOTf, and p-TsOH‚H2O gave
significantly lower yields of cyclized products.
For comparison with the results mentioned above, we
also examined Et2AlCl- and BF3‚Et2O-catalyzed reactions
of epoxytrichloroacetimidates having no substituent at
the 2-position as shown in Table 2.8 In these cases
BF3‚Et2O also caused the production of trichloroacet-
amides 5 or 69 even though cyclizations occurred with
complete regio- and stereoselectivity (entries 2, 4, 6, and
8). Et2AlCl catalyzed reactions again produced oxazo-
lines 3 or dihydrooxazines 4 exclusively, showing its
superiority over BF3‚Et2O in the cyclizations of 2-unsub-
stituted 2,3-epoxytrichloroacetimidates too (entries 1, 3,
5, and 7).
(R)-2-methylglycidol (7)1c of 94% ee,11 followed by piv-
aloylation gave oxazoline 9. It is worthy of note that
BF3‚Et2O catalyzed cyclization of 8 followed by piv-
aloylation afforded the corresponding achiral dipivalate
as a major product (Scheme 3). Oxazoline 9 thus
obtained was then converted into alcohol 10 by acid
hydrolysis followed by tert-butoxycarbonylation in the
same flask. Optical purity11 of 10 (94% ee) showed that
no racemization occurred during the transformation of
7 into 10. After recrystalization from n-hexane, 10
became optically pure. Upon successive Swern oxidation,
NaClO2 oxidation, and esterification, 10 afforded ester
11. Removal of the pivaloyl group of 11 afforded methyl
(R)-N-Boc-methylserinate (12).12
Alcohol 10 was also converted into methyl (S)-N-Boc-
methylserinate (15) as follows (Scheme 4). Methoxy-
methylation of 10 gave methoxymethyl ether 13 which
was then successively subjected to methanolysis, Swern
oxidation, NaClO2 oxidation, and esterification to give 14.
Acid hydrolysis of 14 followed by tert-butoxycarbonylation
gave methyl (S)-N-Boc-methylserinate (15).12
In conclusion, we could establish Et2AlCl-catalyzed
cyclizations of 2,3-epoxytrichloroacetimidates which im-
prove the procedure developed by Schmidt and co-
workers.3 Present study provides a new general strategy
for the enantioselective synthesis of nonproteinogenic
R-substituted serines starting from appropriate allylic
alcohols.
The synthetic utility of newly established Et2AlCl-
catalyzed cyclizations of 2,3-epoxytrichloroacetimidates
was well exhibited by the synthesis of both methyl (R)-
and (S)-N-Boc-methylserinates.10 Thus, Et2AlCl-cata-
lyzed cyclization of trichloroacetimidate 8, prepared from
Exp er im en ta l Section
(7) The structures of 5f and 6f were deduced from the results of
their NaIO4 oxidation.
Gen er a l. All reactions were carried out under an atmosphere
of argon. Extracts were dried over MgSO4 and evaporated under
reduced pressure. Chromatographic purifications were carried
out using Merck silica gel 60 (column) and Merck silica gel 60
PF254 (thin layer). 1H and 13C NMR spectra were recorded in
(8) The stereochemistriy of 3g was determined by NOE experiment
(500 MHz 1H NMR) of the corresponding acetonide of 5g which was
prepared from 3g by acid hydrolysis. 3h and 4i exhibited melting
points, specific rotations, and spectral properties in accord with those
reported.3 The structure of 5h was confirmed by hydrolytic transforma-
tion of 3h into 5h .
(9) BF3‚Et2O-catalyzed cyclizations of various 2-unsubstituted 2,3-
epoxytrichloroacetimidates such as 2h have been examined well by
Schmidt and co-workers.3 However, surprisingly, they did not make
mention of the formation of the corresponding trichloroacetamides in
the cyclizations.
(11) Determined by 1H NMR (500 MHz) analysis of the correspond-
ing (R)- or (S)-R-methoxy-R-(trifluoromethyl)phenylacetates.
(12) Determined to be optically pure by 1H NMR (500 MHz) analysis
of the corresponding (R)- or (S)-R-methoxy-R-(trifluoromethyl)phenyl-
acetates.
(10) This route was employed in our synthesis of (+)-conagenin.2a

Notes
J . Org. Chem., Vol. 62, No. 7, 1997 2277
CDCl3 at 300 and 75 MHz, respectively. Quaternary CCl3 carbon
signals were not detectable in 13C NMR spectra. High-resolution
mass measurements were obtained by electron impact. Optical
rotations were conducted with samples in CHCl3 solution unless
indicated otherwise. Melting points are uncorrected.
P r ep a r a tion of Ep oxytr ich lor oa cetim id a tes 2a -j. To an
ice-cold solution of epoxy alcohol 1 (10 mmol) in CH2Cl2 (60 mL)
were added trichloroacetonitrile (1.1 mL, 11 mmol) and DBU
(0.15 mL, 1.0 mmol). After being stirred at 0 °C until no starting
material was observed on TLC, the reaction mixture was diluted
with Et2O, washed with water, dried, and evaporated. The
residue was immediately used for the next reaction after
filtration through a short silica gel column using a mixture of
n-hexane and AcOEt as eluent.
E t 2AlCl-Ca t a lyzed Cyclyza t ion s of E p oxyt r ich lor o-
a cetim id a tes 2a -j. To an ice-cold solution of epoxytrichrolo-
acetimidate 2 (1.0 mmol) in CH2Cl2 (8 mL) was added Et2AlCl
(0.95 M in hexane, 0.53 mL, 0.5 mmol). After being stirred at
room temperature until no starting material was observed on
TLC, the reaction was quenched with saturated NaHCO3. The
reaction mixture was diluted with Et2O, washed with water,
dried, evaporated, and chromatographed on silica gel using an
appropriate mixture of n-hexane and AcOEt as eluent.
BF 3‚E t 2O-Ca t a lyzed Cyclyza t ion s of E p oxyt r ich lor o-
a cet im id a t es 2a -j. To a stirred solution of epoxytrichloro-
acetimidate 2 (1.0 mmol) in CH2Cl2 (8 mL) at -23 °C was added
BF3‚Et2O (0.06 mL, 0.5 mmol). After being stirred at -23 °C
until no starting material was observed on TLC, the reaction
was quenched with saturated NaHCO3. The reaction mixture
was diluted with Et2O, washed with water, dried, evaporated,
and chromatographed on silica gel using an appropriate mixture
of n-hexane and AcOEt as eluent.
C7H10NO2Cl3: C, 34.29; H, 4.11; N, 5.72. Found: C, 34.37; H,
4.04; N, 5.49.
(2R,3S)-2-Meth yl-2-((tr ich lor oa cetyl)a m in o)bu ta n e-1,3-
1
d iol (5c): [R]21 +2.2° (c ) 0.68); IR 3371, 1703 cm-1; H NMR
D
δ 7.64 (s, 1H), 4.00 (q, 1H, J ) 6.5 Hz), 3.87 (d, 1H, J ) 11.7
Hz), 3.79 (d, 1H, J ) 11.7 Hz), 3.72 (br s, 1H), 3.44 (br s, 1H),
1.33 (s, 3H), 1.28 (d, 3H, J ) 6.5 Hz); 13C NMR δ 162.1, 71.6,
65.4, 61.4, 18.5, 17.8; HRMS m/ z calcd for C6H9NO2Cl3 ([M -
CH2OH]+) 231.9699, found 231.9704.
(4S *,5S *)-4-(H y d r o x y m e t h y l)-4-m e t h y l-5-p h e n y l-2-
1
(tr ich lor om eth yl)-2-oxa zolin e (3d ): IR 3375, 1663 cm-1; H
NMR δ 7.45-7.25 (m, 5H), 5.95 (s, 1H), 3.92 (d, 1H, J ) 11.6
Hz), 3.63 (d, 1H, J ) 11.6 Hz), 2.09 (br s, 1H), 0.81 (s, 3H); 13C
NMR δ 162.4, 135.9, 128.7, 128.6, 125.8, 88.5, 76.3, 68.8, 20.0;
HRMS m/ z calcd for
C
12H12NO2Cl3 (M+) 306.9934, found
306.9936.
(1′S ,4R )-4-(1′-H yd r oxy-1′-p h e n ylm e t h yl)-4-m e t h yl-2-
(tr ich lor om eth yl)-2-oxa zolin e (3e): [R]24 +82.4° (c ) 0.31);
D
IR 3386, 1665 cm-1; 1H NMR δ 7.36-7.26 (m, 5H), 4.93 (d, 1H,
J ) 8.5 Hz), 4.92 (s, 1H), 4.02 (d, 1H, J ) 8.5 Hz), 2.38 (s, 1H),
1.30 (s, 3H); 13C NMR δ 163.0, 138.8, 128.4, 128.4, 127.2, 77.3,
76.7, 76.1, 24.0; HRMS m/ z calcd for C12H12NO2Cl2 ([M - Cl]+)
272.0245, found 272.0238.
(4R,5R)-5-Hyd r oxy-5-m eth yl-4-p h en yl-2-(tr ich lor om eth -
yl)-5,6-d ih yd r o-4H-oxa zin e (4e): [R]23 +44.4° (c ) 0.41); IR
D
3337, 1681 cm-1
;
1H NMR δ 7.40-7.22 (m, 5H), 4.73 (s, 1H),
4.16 (s, 2H), 1.98 (br s, 1H), 0.98 (s, 3H); 13C NMR δ 153.4, 138.0,
128.5, 128.1, 127.8, 72.6, 72.5, 66.8, 21.5; HRMS m/ z calcd for
C
12H12NO2Cl2 ([M - Cl]+) 272.0245, found 272.0245.
(2R,3S)-2-Met h yl-3-p h en yl-2-((t r ich lor oa cet yl)a m in o)-
bu ta n e-1,3-d iol (5e): [R]22D -3.1° (c ) 0.77); IR 3386, 1707 cm-1
;
1H NMR δ 7.39 (s, 1H), 7.37 (s, 5H), 5.13 (s, 1H), 3.81 (d, 1H, J
) 10.4 Hz), 3.69 (br s, 1H), 3.68 (d, 1H, J ) 10.4 Hz), 3.39 (br s,
1H), 1.23 (s, 3H); 13C NMR δ 162.1, 138.8, 128.6, 128.4, 127.5,
77.0, 65.7, 61.6, 18.9; HRMS m/ z calcd for C11H11NO2Cl3 ([M -
Cl]+) 293.9855, found 293.9834.
(1′R,4R)-4-(2′-(Ben zyloxy)-1′-h yd r oxyeth yl)-4-m eth yl-2-
(tr ich lor om eth yl)-2-oxa zolin e (3a ): mp 92-94 °C (n-hexane-
AcOEt); [R]24 +5.9° (c ) 0.99); IR 3351, 1663 cm-1; 1H NMR δ
D
7.38-7.26 (m, 5H), 4.83 (d, 1H, J ) 8.7 Hz), 4.59 (d, 1H, J )
12.0 Hz), 4.50 (d, 1H, J ) 12.0 Hz), 4.22 (d, 1H, J ) 8.7 Hz),
3.94 (dd, 1H, J ) 2.8, 5.9 Hz), 3.71 (dd, 1H, J ) 2.8, 10.1 Hz),
A 25:75 m ixtu r e of (4R)-4-(1′-Hyd r oxy-1′-m eth yleth yl)-
4-m eth yl-2-(tr ich lor om eth yl)-2-oxa zolin e (3f) a n d (5R)-5-
Hyd r oxy-4,4,5-tr im eth yl-2-(tr ich lor om eth yl)-5,6-d ih yd r o-
4H-oxa zin e (4f): 1H NMR δ 4.68 (d, 1 × 0.25H, J ) 8.3 Hz),
4.15 (d, 1 × 0.25H, J ) 8.3 Hz), 4.12 (d, 1 × 0.75H, J ) 11.3
Hz), 4.03 (d, 1 × 0.75H, J ) 11.3 Hz), 1.71 (br s, 1H), 1.30 (s, 3
× 0.25H), 1.27 (s, 3 × 0.75H), 1.20 (s, 3H), 1.17 (s, 3 × 0.75H),
1.13 (s, 3 × 0.25H); 13C NMR δ 3f (minor) 78.5, 78.4, 73.9, 25.0,
24.5, 22.7 and 4f (major) 150.6, 72.2, 69.0, 58.0, 27.0, 23.5, 20.7.
(R)-2,3-Dim eth yl-2-((tr ich lor oa cetyl)a m in o)bu ta n e-1,3-
3.57 (dd, 1H, J ) 5.9, 10.1 Hz), 2.61 (br s, 1H), 1.31 (s, 3H); 13
C
NMR δ 162.8, 137.7, 128.6, 128.0, 127.8, 78.7, 74.3, 74.2, 73.8,
70.4, 22.3; HRMS m/ z calcd for C14H16NO3Cl2 ([M - Cl]+)
316.0507, found 316.0573. Anal. Calcd for C14H16NO3Cl3: C,
47.08; H, 4.57; N, 3.97; Cl, 30.16. Found: C, 47.19; H, 4.47; N,
3.90; Cl, 29.76.
(2R ,3R )-4-(Be n zyloxy)-2-m e t h yl-2-((t r ich lor oa ce t yl)-
a m in o)bu ta n e-1,3-d iol (5a ): [R]16 -3.4° (c ) 0.93); IR 3376,
D
1707 cm-1; H NMR δ 7.80 (s, 1H), 7.38-7.30 (m, 5H), 4.56 (s,
1
d iol (5f): [R]16 -15.2° (c ) 0.16); IR 3366, 1704 cm-1; 1H NMR
D
2H), 4.00 (dd, 1H, J ) 5.8, 6.4 Hz), 3.82 (d, 1H, J ) 12.0 Hz),
3.73 (d, 1H, J ) 12.0 Hz), 3.63 (dd, 1H, J ) 5.8, 10.2 Hz), 3.59
(dd, 1H, J ) 6.4, 10.2 Hz), 1.36 (s, 3H); 13C NMR δ 162.2, 136.9,
128.7, 128.3, 128.2, 73.9, 73.4, 70.3, 65.5, 61.1, 17.7; HRMS m/ z
δ 7.85 (br s, 1H), 4.05 (d, 1H, J ) 11.8 Hz), 3.78 (d, 1H, J ) 11.8
Hz), 3.30 (s, 1H), 2.75 (br s, 1H), 1.30 (s, 3H), 1.27 (s, 3H), 1.18
(s, 3H); 13C NMR δ 166.0, 75.9, 65.1, 63.2, 25.0, 24.9, 17.4; HRMS
m/ z calcd for C7H11NO2Cl3 ([M - CH2OH]+) 245.9855, found
245.9821.
calcd for
338.0116.
C
13H15NO3Cl3 ([M - CH2OH]+) 338.0117, found
(R)-2,3-Dim eth yl-3-((tr ich lor oa cetyl)a m in o)bu ta n e-1,2-
(1′S ,4R )-4-(2′-Me t h yl-1′-h yd r oxyp r op yl)-4-m e t h yl-2-
(tr ich lor om eth yl)-2-oxa zolin e (3b): mp 44-47 °C (n-hexane-
1
d iol (6f): [R]16 +3.7° (c ) 0.44); IR 3357, 1704 cm-1; H NMR
D
AcOEt); [R]17 +1.0° (c ) 0.98); IR 3448, 1662 cm-1; 1H NMR δ
δ 7.63 (br s, 1H), 3.73 (d, 1H, J ) 11.0 Hz), 3.56 (d, 1H, J ) 11.0
Hz), 3.45 (br s, 1H), 2.40 (br s, 1H), 1.46 (s, 6H), 1.24 (s, 3H);
13C NMR δ 161.7, 76.1, 66.2, 61.0, 21.7, 21.6, 20.3; HRMS m/ z
calcd for C7H11NO2Cl3 ([M - CH2OH]+) 245.9855, found 245.9839.
(1′R,4R)-4-(2′-(Ben zyloxy)-1′-h yd r oxyet h yl)-2-(t r ich lo-
D
4.80 (d, 1H, J ) 8.2 Hz), 4.22 (d, 1H, J ) 8.2 Hz), 3.77 (dd, 1H,
J ) 3.1, 4.4 Hz), 1.93 (m, 1H), 1.78 (d, 1H, J ) 4.4 Hz), 1.33 (s,
3H), 1.07 (d, 3H, J ) 6.9 Hz), 0.83 (d, 3H, J ) 6.9 Hz); 13C NMR
δ 162.1, 78.5, 76.9, 76.1, 28.9, 23.7, 21.3, 15.8; HRMS m/ z calcd
for C6H7NO2Cl3 ([M - C3H7]+) 229.9542, found 229.9537. Anal.
Calcd for C9H14NO2Cl3: C, 39.56; H, 5.17; N, 5.13; Cl, 38.43.
Found: C, 39.31; H, 4.95; N, 5.08; Cl, 38.45.
r om eth yl)-2-oxa zolin e (3g): mp 57-59 °C (n-hexane-AcOEt);
1
[R]24 -38.3° (c ) 0.89); IR 3341, 1658 cm-1; H NMR δ 7.39-
D
7.29 (m, 5H), 4.71 (dd, 1H, J ) 8.3, 8.7 Hz), 4.63 (dd, 1H, J )
9.7, 8.7 Hz), 4.57 (s, 2H), 4.41 (ddd, 1H, J ) 6.1, 8.3, 9.7 Hz),
3.99 (m, 1H), 3.69 (dd, 1H, J ) 3.9, 9.6 Hz), 3.62 (dd, 1H, J )
6.0, 9.6 Hz), 2.43 (br s, 1H); 13C NMR δ 164.1, 137.7, 128.6, 128.0,
(2R,3S)-2,4-Dim eth yl-2-((tr ich lor oacetyl)am in o)pen tan e-
1,3-d iol (5b): [R]17 +1.8° (c ) 0.67); IR 3429, 3351, 1697 cm-1
;
D
1H NMR δ 7.62 (s, 1H), 3.93 (d, 1H, J ) 11.0 Hz), 3.75 (br s,
1H), 3.73 (d, 1H, J ) 11.0 Hz), 3.62 (br s, 1H), 2.67 (br s, 1H),
1.93 (m, 1H), 1.39 (s, 3H), 1.05 (d, 3H, J ) 6.9 Hz), 1.01 (d, 3H,
J ) 6.9 Hz); 13C NMR δ 161.8, 79.2, 65.9, 62.2, 28.9, 22.4, 19.7,
16.6; HRMS m/ z calcd for C8H13NO2Cl3 ([M - CH2OH]+)
260.0012, found 260.0010.
127.9, 73.7, 73.1, 71.5, 71.4, 69.0; HRMS m/ z calcd for C13H13
NO3Cl3 ([M - H]+) 336.0039, found 335.9981. Anal. Calcd for
13H14NO3Cl3: C, 46.11; H, 4.17; N, 4.14; Cl, 31.41. Found: C,
-
C
45.75; H, 4.11; N, 4.15; Cl, 31.23.
(2R,3R)-4-(Ben zyloxy)-2-((tr ich lor oacetyl)am in o)bu tan e-
(1′S,4R)-4-(1′-Hydr oxyeth yl)-4-m eth yl-2-(tr ich lor om eth yl)-
1,3-d iol (5g): [R]16 +9.3° (c ) 0.09); IR 3340, 1699 cm-1 1H
;
D
2-oxa zolin e (3c): mp 75-78 °C (n-hexane-AcOEt); [R]24D +5.3°
NMR δ 7.45 (d, 1H, J ) 8.2 Hz), 7.38-7.26 (m, 5H), 4.53 (s,
2H), 4.22 (m, 1H), 4.00 (m, 1H), 3.89 (dd, 1H, J ) 3.6, 11.2 Hz),
3.80 (dd, 1H, J ) 5.4, 11.2 Hz), 3.55 (dd, 1H, J ) 4.8, 9.6 Hz),
3.46 (dd, 1H, J ) 7.4, 9.6 Hz); 13C NMR δ 162.5, 137.1, 128.7,
128.3, 128.2, 74.0, 71.2, 70.8, 61.5, 54.6; HRMS m/ z calcd for
1
(c ) 0.15); IR 3427, 1659 cm-1; H NMR δ 4.71 (d, 1H, J ) 8.3
Hz), 4.22 (d, 1H, J ) 8.3 Hz), 3.99 (q, 1H, J ) 6.6 Hz), 2.02 (br
s, 1H), 1.34 (s, 3H), 1.17 (d, 3H, J ) 6.6 Hz); 13C NMR δ 162.8,
76.8, 76.1, 71.3, 23.1, 16.9; HRMS m/ z calcd for C6H7NO2Cl3
([M - CH3]+) 231.9699, found 231.9679. Anal. Calcd for
C
13H16NO4Cl2 ([M - Cl]+) 320.0456, found 320.0449.

2278 J . Org. Chem., Vol. 62, No. 7, 1997
Notes
(1′S ,4R )-4-(2′-Me t h yl-1′-h yd r oxyp r op yl)-2-(t r ich lor o-
m eth yl)-2-oxa zolin e (3h ): mp 63-64 °C (n-hexane-AcOEt)
(lit.3 mp 67 °C); [R]25 -68.8° (c ) 0.10) {lit.3 [R]20 -70.5° (c )
mmol) was added. After 19 h, the reaction mixture was
saturated with NaCl, extracted with AcOEt, dried, and chro-
matographed on silica gel. Elution with 5:1 n-hexane-AcOEt
gave 10 (1.33 g, 91%) as a colorless powder: mp 110-112 °C
D
D
1.74)}; IR 3405, 1651 cm-1; 1H NMR δ 4.68 (dd, 1H, J ) 8.3, 8.9
Hz), 4.62 (dd, 1H, J ) 8.3, 9.6 Hz), 4.51 (ddd, 1H, J ) 3.2, 8.9,
9.6 Hz), 3.72 (dd, 1H, J ) 3.2, 7.4 Hz), 1.85 (br s, 1H), 1.72 (oct,
1H, J ) 6.9 Hz), 1.04 (d, 3H, J ) 6.9 Hz), 0.94 (d, 3H, J ) 6.9
Hz); 13C NMR δ 164.0, 76.7, 71.6, 69.5, 30.8, 19.0, 18.6; HRMS
m/ z calcd for C8H13NO2Cl3 ([M + H]+) 259.9934, found 259.9962.
13C and 1H NMR data were identical with those reported.3
(2R,3S)-4-Meth yl-2-((tr ich lor oa cetyl)a m in o)p en ta n e-1,3-
d iol (5h ): [R]16D -81.0° (c ) 0.89); IR 3408, 1696 cm-1; 1H NMR
δ 7.66 (br s, 1H), 4.12 (dd, 1H, J ) 2.4, 11.5 Hz), 4.02 (m, 1H),
3.87 (dd, 1H, J ) 3.0, 11.5 Hz), 3.49 (dd, 1H, J ) 3.9, 8.5 Hz),
2.71 (br s, 2H), 1.86 (m, 1H), 1.07 (d, 3H, J ) 6.6 Hz), 0.98 (d,
3H, J ) 6.6 Hz); 13C NMR δ 162.0, 79.0, 61.6, 53.0, 31.5, 19.1,
18.7; HRMS m/ z calcd for C7H11NO2Cl3 ([M - CH2OH]+)
245.9855, found 245.9839.
(n-hexane); [R]25 +8.8° (c ) 0.38); IR 3255, 1724, 1677 cm-1
;
D
1H NMR δ 4.84 (s, 1H), 4.25 (d, 1H, J ) 11.2 Hz), 4.20 (d, 1H,
J ) 11.2 Hz), 3.82 (br, 1H), 3.61 (dd, 1H, J ) 6.6, 11.8 Hz), 3.55
(dd, 1H, J ) 6.9, 11.8 Hz), 1.43 (s, 9H), 1.26 (s, 3H), 1.23 (s,
9H); 13C NMR δ 178.7, 155.7, 80.1, 67.1, 65.8, 56.4, 39.0, 28.4,
27.2, 20.1; HRMS m/ z calcd for C13H24NO4 ([M - CH2OH]+)
258.1705, found 258.1704. Anal. Calcd for C14H27NO5: C, 58.11;
H, 9.41; N, 4.84. Found: C, 58.04; H, 9.30; N, 4.81.
Meth yl (R)-2-((ter t-Bu toxyca r bon yl)a m in o)-2-m eth yl-3-
(p iva loyloxy)p r op ion a te (11): To a stirred solution of oxalyl
chloride (0.088 mL, 1.00 mmol) in CH2Cl2 (5 mL) at -60 °C was
added DMSO (0.155 mL, 2.01 mmol). The mixture was stirred
at the same temperature for 15 min, and then 10 (145 mg, 0.502
mmol) was added. After being stirred at -60 °C for 40 min, the
reaction mixture was treated with Et3N (0.349 mL, 2.51 mmol)
and allowed to warm to room temperature. The reaction mixture
was diluted with AcOEt, washed with water, dried, and evapo-
rated to give the aldehyde as a pale yellow oil (168 mg). To a
solution of the crude aldehyde (168 mg) in 20% aqueous t-BuOH
(5 mL) were added NaH2PO4‚H2O (137 mg, 0.878 mmol),
2-methyl-2-butene (0.371 mL, 3.51 mmol), and NaClO2 (263 mg,
2.31 mmol). After being stirred at room temperature for 1 h,
the reaction mixture was acidified with 4% HCl and extracted
with AcOEt. The extract was washed with water, dried, and
evaporated. The residue was dissolved in Et2O, and a solution
of diazomethane in Et2O was added to the mixture until no
carboxylic acid was observed on TLC. The reaction mixture was
evaporated and purified by silica gel preparative TLC developed
with 5:1 n-hexane-AcOEt to give 11 (115 mg, 72%) as a colorless
(4R,5S)-5-Hyd r oxy-4-p h en yl-5,6-d ih yd r o-4H-oxa zin e (4i):
mp 123-125 °C (n-hexane-AcOEt) (lit.3 mp 120 °C); [R]24
D
+87.4° (c ) 0.85) {lit.3 [R]20 +91.3° (c ) 2.40)}; IR 3338, 1671
D
cm-1; 1H NMR δ 7.43-7.20 (m, 5H), 4.74 (br d, 1H, J ) 4.1 Hz),
4.30 (dd, 1H, J ) 3.1, 11.2 Hz), 4.23 (ddd, 1H, J ) 1.5, 5.0, 11.2
Hz), 3.93 (m, 1H), 2.20 (br s, 1H); 13C NMR δ 154.2, 139.4, 129.0,
128.1, 127.1, 67.8, 66.9, 62.8; HRMS m/ z calcd for C11H10NO2-
Cl3 (M+) 292.9777, found 292.9920. Anal. Calcd for C7H10NO2-
Cl3: C, 44.85; H, 3.42; N, 4.76; Cl, 36.11. Found: C, 44.41; H,
3.42; N, 4.61; Cl, 35.87.
(R)-4,4-Dim et h yl-5-h yd r oxy-2-(t r ich lor om et h yl)-5,6-d i-
h yd r o-4H-oxa zin e (4j): mp 127-130 °C (n-hexane-AcOEt);
[R]24 +16.3° (c ) 0.98); IR 3390, 1660 cm-1 1H NMR δ 4.42
;
D
(dd, 1H, J ) 3.0, 11.4 Hz), 4.27 (dd, 1H, J ) 4.8, 11.4 Hz), 3.77
(br s, 1H), 1.89 (br s, 1H), 1.33 (s, 3H), 1.31 (s, 3H); 13C NMR δ
viscous oil: [R]17 -10.5° (c ) 0.89); IR 3379, 1736, 1714 cm-1
;
151.0, 68.5, 68.1, 54.8, 28.5, 24.4; HRMS m/ z calcd for C7H11
-
D
1H NMR δ 5.37 (br s, 1H), 4.54 (d, 1H, J ) 10.3 Hz), 4.35 (d,
1H, J ) 10.3 Hz), 3.76 (s, 3H), 1.55 (s, 3H), 1.43 (s, 9H), 1.18 (s,
9H); 13C NMR δ 177.7, 172.9, 154.2, 79.9, 65.6, 59.2, 52.8, 38.8,
28.3, 27.1, 20.5; HRMS m/ z calcd for C15H28NO6 ([M + H]+)
318.1917, found 318.1913.
NO2Cl3 ([M + H]+) 245.9777, found 245.9793. Anal. Calcd for
C7H10NO2Cl3: C, 34.11; H, 4.09; N, 5.68; Cl, 43.14. Found: C,
33.97; H, 3.99; N, 5.67; Cl, 42.88.
(R )-3-Me t h y l-3-((t r ic h lo r o a c e t y l)a m in o )b u t a n e -1,2-
d iol (6j): [R]23 +0.3° (c ) 0.67), [R]25 -1.2° (c ) 0.67, MeOH);
D
D
1
IR 3375, 1698 cm-1; H NMR δ 7.26 (br s, 1H), 3.83 (dd, 1H, J
) 2.2, 10.7 Hz), 3.74 (br d, 1H, J ) 7.4 Hz), 3.62 (dd, 1H, J )
7.4, 10.7 Hz), 2.52 (br s, 1H), 1.84 (br s, 1H), 1.50 (s, 3H), 1.43
(s, 3H); 13C NMR δ 161.7, 76.6, 62.5, 57.8, 23.5, 22.7; HRMS
m/ z calcd for C6H9NO2Cl3 ([M - CH2OH]+) 231.9699, found
231.9705.
Met h yl (R)-N-(ter t-Bu t oxyca r b on yl)-2-m et h ylser in a t e
(12): To a solution of 11 (53 mg, 0.167 mmol), in MeOH (2 mL)
was added K2CO3 (23 mg, 0.167 mmol) and the mixture was
stirred at room temperature for 1 h. The reaction mixture was
diluted with AcOEt, washed with water, dried, and evaporated.
Purification by silica gel preparative TLC developed with 3:1
n-hexane-AcOEt gave 12 (27 mg, 70%) as a colorless viscous
(S)-4-Meth yl-4-((pivaloyloxy)m eth yl)-2-(tr ich lor om eth yl)-
2-oxa zolin e (9): To an ice-cold solution of (R)-methylglycidol
(7) (638 mg, 7.24 mmol, 94% ee) in CH2Cl2 (45 mL) were added
trichloroacetonitrile (0.80 mL, 7.96 mmol) and DBU (0.11 mL,
0.72 mmol). After being stirred at 0 °C for 1.5 h, the reaction
mixture was diluted with Et2O, washed with water, dried, and
chromatographed on silica gel. Elution with 20:1 hexane-
AcOEt gave trichloroacetimidate 8 (1.73 g).
oil: [R]18 -2.0° (c ) 0.81); IR 3373, 1713 cm-1; 1H NMR δ 5.45
D
(br s, 1H), 3.93 (br d, 1H, J ) 11.0 Hz), 3.78 (br d, 1H, J ) 11.0
Hz), 3.77 (s, 3H), 1.47 (s, 3H), 1.44 (s, 9H); 13C NMR δ 174.0,
155.5, 80.3, 66.9, 61.0, 52.7, 28.3, 20.8; HRMS m/ z calcd for
C9H17NO4 ([M - CH2O]+) 203.1158, found 203.1159.
(S)-2-((ter t-Bu t oxyca r b on yl)a m in o)-2-m et h yl-3-(m et h -
oxym eth oxy)-1-(p iva loyloxy)p r op a n e (13): To a solution of
10 (375 mg, 1.30 mmol) in CH2Cl2 (15 mL) were added diiso-
propylethylamine (2.3 mL, 13.0 mmol) and chloromethyl methyl
ether (0.50 mL, 6.5 mmol). After being stirred at room temper-
ature for 2 h, the reaction mixture was diluted with AcOEt,
washed with water, dried, and chromatographed on silica gel.
Elution with 3:1 n-hexane-AcOEt gave 13 (408 mg, 94%) as a
To an ice-cold solution of 8 (1.73 g) in CH2Cl2 (58 mL) was
added Et2AlCl (0.95 M in hexane, 3.93 mL, 3.73 mmol). After
the mixture was stirred at 0 °C for 20 min and then at room
temperature for 3 h, the reaction was quenched with saturated
NaHCO3. The reaction mixture was diluted with Et2O, washed
with water, dried, and evaporated. The crystalline residue (2.0
g) was dissolved in CH2Cl2 (15 mL), and Et3N (3.0 mL, 21.5
mmol), DMAP (2 mg, 0.016 mmol), and pivaloyl chloride (1.8
mL, 14.6 mmol) were added to the solution. After the mixture
was stirred at room temperature for 2.5 h, the reaction mixture
was diluted with Et2O, washed with water, dried, and chro-
matographed on silica gel. Elution with 10:1 hexane-AcOEt
gave 9 (1.86 g, 82%) as colorless crystals: mp 50-53 °C
(n-hexane); [R]24D +32.5° (c ) 1.14); IR 1733, 1662 cm-1; 1H NMR
δ 4.56 (d, 1H, J ) 8.5 Hz), 4.27 (d, 1H, J ) 8.5 Hz), 4.13 (s, 2H),
1.43 (s, 3H), 1.21 (s, 9H); 13C NMR δ 178.1, 162.4, 78.2, 75.2,
71.2, 68.2, 39.0, 27.2, 23.5; HRMS m/ z calcd for C11H16NO3Cl3
(M+) 315.0196, found 315.0181. Anal. Calcd for C11H16NO3-
Cl3: C, 41.73; H, 5.09; N, 4.42; Cl, 33.59. Found: C, 41.61; H,
5.02; N, 4.26; Cl, 33.37.
yellow oil: [R]25 -4.6° (c ) 1.49); IR 3374, 1723, 1151 cm-1; 1H
D
NMR δ 4.86 (s, 1H), 4.62 (s, 2H), 4.26 (d, 1H, J ) 10.8 Hz), 4.18
(d, 1H, J ) 10.8 Hz), 3.63 (d, 1H, J ) 9.6 Hz), 3.50 (d, 1H, J )
9.6 Hz), 3.35 (s, 3H), 1.43 (s, 9H), 1.37 (s, 3H), 1.21 (s, 9H); 13
C
NMR δ 177.9, 154.6, 96.8, 79.4, 70.7, 65.6, 55.4, 54.8, 38.9, 28.4,
27.2, 19.5; HRMS m/ z calcd for C16H31NO6 ([M + H]+) 334.2230,
found 334.2273.
Meth yl (S)-2-((ter t-Bu toxyca r bon yl)a m in o)-2-m eth yl-3-
(m eth oxym eth oxy)p r op ion a te (14): To a solution of 13 (192
mg, 0.577 mmol) in MeOH (5 mL) was added K2CO3 (80 mg,
0.577 mmol), and the mixture was stirred at room temperature
for 12 h. The reaction mixture was diluted with AcOEt, washed
with water, dried, and evaporated to give the corresponding
alcohol (128 mg) as a colorless oil. To a stirred solution of oxalyl
chloride (0.090 mL, 1.03 mmol) in CH2Cl2 (5 mL) at -60 °C was
added DMSO (0.159 mL, 2.03 mmol). The mixture was stirred
at the same temperature for 15 min, and then a solution of crude
alcohol (128 mg) in CH2Cl2 (5 mL) was added. After being
stirred at -60 °C for 40 min, the reaction mixture was treated
(S )-2-((t er t -Bu t oxyca r b on yl)a m in o)-2-m e t h yl-3-(p iv-
a loyloxy)p r op a n ol (10): To a solution of 8 (1.60 g, 5.05 mmol)
in THF (30 mL) was added 1 M HCl (5 mL). After being stirred
at room temperature for 2 h, the reaction mixture was carefully
basified with NaHCO3 (6.6 g) and then Boc2O (3.30 g, 15.14

Notes
J . Org. Chem., Vol. 62, No. 7, 1997 2279
with Et3N (0.358 mL, 2.57 mmol) and allowed to warm to room
temperature. The reaction mixture was diluted with AcOEt and
successively washed with 4% HCl, water, and saturated NaH-
CO3. The organic layer was dried and evaporated to give the
aldehyde as a pale yellow oil (127 mg). To a solution of crude
aldehyde (127 mg) in 20% aqueous t-BuOH (5 mL) were added
NaH2PO4‚H2O (120 mg, 0.771 mmol), 2-methyl-2-butene (0.326
mL, 3.08 mmol), and NaClO2 (231 mg, 2.06 mmol). After being
stirred at room temperature for 1 h, the reaction mixture was
acidified with 4% HCl and extracted with AcOEt. The extract
was washed with water, dried, and evaporated. The residue was
dissolved in Et2O, and a solution of diazomethane in Et2O was
added to the mixture until no carboxylic acid was observed on
TLC. The reaction mixture was evaporated and purified by silica
gel preparative TLC developed with 1:1 n-hexane-AcOEt to give
14 (99 mg, 62%) as a colorless viscous oil: [R]17D -4.6° (c ) 0.93);
Met h yl (S)-N-(ter t-Bu t oxyca r b on yl)-2-m et h ylser in a t e
(15): To a solution of 14 (57 mg, 0.207 mmol) in THF (2 mL)
was added concd HCl (0.3 mL), and the mixture was stirred at
room temperature for 4 h. The reaction mixture was carefully
basified with NaHCO3, and then Boc2O (135 mg, 0.413 mmol)
was added. After 12 h, the reaction mixture was saturated with
NaCl, extracted with AcOEt, dried, and evaporated. Purification
by silica gel preparative TLC developed with 1:1 hexane-AcOEt
gave 15 (27 mg, 64%) as a colorless viscous oil: [R]18 +1.9° (c
D
) 0.54). The spectral data were identical with those of 12.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of 3a -e, 3g/h , 4e/i/j, 3f/4f (mixture), 5a -c, 5e-h , 6f/
j, and 9-15 (81 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
IR 3370, 1742, 1719 cm-1 1H NMR δ 5.41 (br s, 1H), 4.54 (s,
;
2H), 3.79 (d, 1H, J ) 9.8 Hz), 3.73 (d, 1H, J ) 9.8 Hz), 3.70 (s,
3H), 3.26 (s, 3H), 1.48 (s, 3H), 1.37 (s, 9H); 13C NMR δ 173.4,
154.7, 96.7, 79.7, 70.9, 59.9, 55.4, 52.7, 28.4, 20.5; HRMS m/ z
calcd for C12H24NO6 ([M + H]+) 278.1604, found 278.1624.
J O9618278